Modulation of aflatoxin-B1 hepatocarcinogenesis in trout by dehydroepiandrosterone: initiation/post-initiation and latency effects.
Previously, we demonstrated that dehydroepiandrosterone (DHEA) enhances aflatoxin B1 (AFB1) hepatocarcinogenesis in trout when administered following AFB1 exposure. This paper examines the effect of DHEA on tumor latency and the comparative potency for DHEA to modulate AFB1 carcinogenesis when administered prior to and concurrent with AFB1 compared with a post-initiation exposure. Trout were initiated by a 30 min water bath exposure to 10 p.p.b. AFB1. At 3 months post-initiation, animals were started on either control diet or a diet containing 444 p.p.m. dehydroepiandrosterone (DHEA). Fifty trout per treatment were sampled prior to the start of experimental diets, and then at monthly intervals for the next 7 months and examined for the presence of tumors. Tumors were not detected in initiated controls until 7 months after initiation. In initiated trout fed DHEA, the first tumor was detected 5 months after initiation (after just 2 months of dietary DHEA). At 6 months post-initiation, 20% of the AFB1-initiated trout fed DHEA had tumors, while no tumors were visible in either AFB1-initiated controls or noninitiated trout fed DHEA. A second experiment was designed to determine if the enhancing effect of DHEA on AFB1 carcinogenesis is dependent on the time of DHEA administration relative to the time of AFB1 exposure, and if DHEA could be chemopreventive if administered prior to and concurrent with AFB1. Trout were fed one of two levels of DHEA (888 or 1776 p.p.m.) either prior to and during a 4-week initiation period of dietary AFB1 administration, or for 8 weeks following initiation with AFB1. At 9 months after initiation the livers were examined for tumors. Neither exposure protocol provided protection towards AFB1 hepatocarcinogenesis. The strongest enhancement occurred when DHEA was fed during the post-initiation period. Levels of p53 and p34cdc2 were decreased by DHEA treatment, indicating that DHEA may act through alterations in cell-cycle control.
Orner
G A
GA
Toxicology Program, Oregon State University, Corvallis 97331-6602, USA.
Hendricks
J D
JD
Arbogast
D
D
Williams
D E
DE
D016604:Aflatoxin B1 / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D016203:CDC2 Protein Kinase / Q000032:analysis; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D002453:Cell Cycle; D003687:Dehydroepiandrosterone / Q000008:administration & dosage / Q000633:toxicity*; D004032:Diet; D004334:Drug Administration Schedule; D004357:Drug Synergism; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000473:pathology*; D013997:Time Factors; D014337:Trout; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000096:biosynthesis
D002273:Carcinogens; D016159:Tumor Suppressor Protein p53; D003687:Dehydroepiandrosterone; D016604:Aflatoxin B1; D016203:CDC2 Protein Kinase